Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, members of which exert prompt stimulatory action on smooth muscle tissue. Substance P is a pharmaceutical active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence that is described in U.S. Pat. No. 4,680,283. A variety of substance P antagonists can be prepared from the title compound. For example, U.S. Pat. No. 5,323,929 describes Substance P antagonists of formula 2 where R1 is a substituted or unsubstituted aryl, heteroaryl, or cycloalkyl group. 
These antagonists can be prepared by reduction of 2-phenyl-3-aminopyridine followed by the reductive amination of the resulting 2-phenyl-3 aminopiperidine using the appropriate aldehyde of formula R1CH2CHO. Alternatively, these substance P antagonists can be obtained by reacting 2-phenyl-3-aminopyridine with a compound of the formula R1CH2X where X is a leaving group to produce the pyridine analog of the substance antagonist. The pyridine analog is then reduced to obtain the final product.
Additional substance P antagonists that can be prepared from 2-phenyl-3-amino piperidine are described in U.S. Pat. No. 5,773,450, and PCT Applications WO 97/08144 and WO 01/77100. Methods employing 2-phenyl-3-amino piperidine to make substance P are also described in U.S. Pat. No. 5,232,929. The conventional method employed to prepare 2-phenyl-3-amino piperidine is described by Miller and Farrell (Tetrahedron Letters, 1998, 39, 6441-6444), is sensitive to air and results in a relatively low yield. In many cases, a late stage resolution has to be undertaken to obtain the active isomer, as for example, see Eur. Pat. Appl 1095939. The cis configuration of the amino and phenyl substituents is accessible by catalytic hydrogenation of the appropriately substituted pyridine compound as described in WO 92/17449, WO 93/01170 and U.S. Pat. No. 5,686,615. However, this method provides the racemic material which then has to be resolved as described in WO 94/27966.
A racemic analog of the desired amine has been prepared by a nitroaldol reaction followed by conversion of the trans-nitro compound to the cis amino compound by a Nef reaction followed by reduction of the oxime (see WO 93/01170 and Tetrahedron Letters, 1993, 34, 5831; a related reaction is given in Synthesis 1976, 615 and Journal of Prak Chemistry 1975, 317, 919).
A synthesis of 2 has been described from (S)-N,N-dibenzyl-O-tert-butyldimethylserinol (Tetrahedron Letters, 1999, 40, 5071) but the sequence involves nine steps. The key cyclization involves a displacement reaction. Phenylglycine methyl ester has also been used as the starting material to prepare an analogue of 2 (Synthesis, 1997, 475), with a 4-isopropyl substituent. In this case, the carboxylic acid provides an alcohol which is then substituted for the 3-amino group. A 4-substituent is necessary as the key cyclization step is an ene reaction.
Alkylation of (4R)-4-phenyl-2-azetidinone with 1-bromo-3-chloropropane followed by hydrolysis of the lactam and cyclization resulted in formation of a cis-piperidine derivative, but then a four step sequence was required to stereoselectively convert the carbomethoxy group to amino (see WO 93/01170 and Journal of Medicinal Chemistry 1992, 35, 4911).
Ornithine has been used to prepare piperidinones where homologation was performed with the lithium enolate of ethyl acetate. Removal of the protecting Cbz group by hydrogenolysis and in situ reduction of the imine led to the trans-product as summarized in Scheme 1 (Tetrahedron Letters 1993, 34, 3593 and 1992, 32, 1089; Journal of Medicinal Chemistry, 1997, 40, 3402). 
Reduction of the azide group in (S)-5-azido-2-hydroxy-1-phenyl-1-pentanone resulted in formation of a 4:1 mixture of the cis/trans 3-hydroxy-2-phenylpiperidine (Heterocycles 1999, 51, 1067).